An impressive body of evidence supports the notion that chemoprevention has the potential to be a major component of control of cancer, including pancreatic cancer, one of the most lethal cancers. We propose to study phospho-valproic acid (P-V), a novel derivative of valproic acid, as an agent for the prevention of pancreatic cancer. P-V inhibits the growth of human cancer cell lines up to 245-fold more potently than VPA. In animal models, P-V is twice as effective against pancreatic cancer as VPA. For example, in xenograft models P-V reduced tumor volume by 68%, compared to control, whereas VPA reduced it by 34% (chemoprevention protocol). Remarkably, when given in combination with cimetidine, a clinically available antiulcer compound, P-V prevented 100% of pancreatic tumors in the same animal model. P-V appears to be safe, as shown by genotoxicity and animal toxicity studies. Its mechanism of action is complex, involving several signaling cascades, most prominently STAT3. Our hypothesis is that P-V 1 cimetidine is an effective and safe chemopreventive agent against pancreatic cancer, acting primarily through the STAT3 pathway. To test this hypothesis, we will pursue the following specific aims:
Specific Aim # 1: Determine the chemopreventive efficacy of P-V 1 cimetidine in preclinical models of pancreatic cancer;
Specific Aim # 2: Determine the mechanism of action of P-V 1 cimetidine in vitro and in vivo;
Specific Aim # 3: Determine the metabolism of P-V 1 cimetidine in cultured pancreatic cancer cells and animals and its safety in animals. At the completion of these studies, we expect to have determined key pharmacological parameters of a promising novel agent and its combination with cimetidine. Given the importance of pancreatic cancer and the lack of effective agents against it, we believe that the proposed work holds the promise of a significant advance in this area.
An impressive body of evidence supports the notion that chemoprevention has the potential to be a major component of control of cancer, including pancreatic cancer, one of the most lethal cancers. We propose to study phospho-valproic acid (P-V), a novel derivative of valproic acid, as an agent for the prevention of pancreatic cancer. Given the importance of pancreatic cancer and the lack of effective agents against it, we believe that the proposed work holds the promise of a significant advance in this area.
|Mattheolabakis, George; Papayannis, Ioannis; Yang, Jennifer et al. (2016) Phospho-Aspirin (MDC-22) Prevents Pancreatic Carcinogenesis in Mice. Cancer Prev Res (Phila) 9:624-34|
|Bartels, Lauren E; Mattheolabakis, George; Vaeth, Brandon M et al. (2016) The novel agent phospho-glycerol-ibuprofen-amide (MDC-330) inhibits glioblastoma growth in mice: an effect mediated by cyclin D1. Carcinogenesis 37:420-429|
|Wong, Chi C; Cheng, Ka-Wing; Papayannis, Ioannis et al. (2015) Phospho-NSAIDs have enhanced efficacy in mice lacking plasma carboxylesterase: implications for their clinical pharmacology. Pharm Res 32:1663-75|
|Mackenzie, Gerardo G; Huang, Liqun; Alston, Ninche et al. (2013) Targeting mitochondrial STAT3 with the novel phospho-valproic acid (MDC-1112) inhibits pancreatic cancer growth in mice. PLoS One 8:e61532|
|Mackenzie, Gerardo G; Bartels, Lauren E; Xie, Gang et al. (2013) A novel Ras inhibitor (MDC-1016) reduces human pancreatic tumor growth in mice. Neoplasia 15:1184-95|
|Wong, Chi C; Cheng, Ka-Wing; Xie, Gang et al. (2012) Carboxylesterases 1 and 2 hydrolyze phospho-nonsteroidal anti-inflammatory drugs: relevance to their pharmacological activity. J Pharmacol Exp Ther 340:422-32|
|Zhu, Rongrong; Cheng, Ka-Wing; Mackenzie, Gerardo et al. (2012) Phospho-sulindac (OXT-328) inhibits the growth of human lung cancer xenografts in mice: enhanced efficacy and mitochondria targeting by its formulation in solid lipid nanoparticles. Pharm Res 29:3090-101|
|Cheng, Ka Wing; Mattheolabakis, George; Wong, Chi C et al. (2012) Topical phospho-sulindac (OXT-328) is effective in the treatment of non-melanoma skin cancer. Int J Oncol 41:1199-203|
|Wong, C C; Cheng, Ka-Wing; Rigas, Basil (2012) Preclinical predictors of anticancer drug efficacy: critical assessment with emphasis on whether nanomolar potency should be required of candidate agents. J Pharmacol Exp Ther 341:572-8|
|Sun, Yu; Huang, Liqun; Mackenzie, Gerardo G et al. (2011) Oxidative stress mediates through apoptosis the anticancer effect of phospho-nonsteroidal anti-inflammatory drugs: implications for the role of oxidative stress in the action of anticancer agents. J Pharmacol Exp Ther 338:775-83|
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